4-aminobenzopyran derivatives

ABSTRACT

This invention relates to benzopyran derivatives of the formula (I) wherein, R 1  and R 2  represent each independently a C 1-6 alkyl group, etc, R 3  represents a hydroxyl group, etc, R 4  represents a hydrogen atom, etc, R 6  represents a hydrogen atom, R 7  represents a hydrogen atom, etc, X is absent, or represents C═O, etc, R 8  represents a hydrogen atom, a C 1-6 alkyl group, etc, R 9  represents a hydrogen atom or a nitro group, when R 9  represents a nitro group, Y represents a C 4-8 alkylene group, —(CH 2 ) m —CR 11 R 12 —(CH 2 ) n — or —(CH 2 ) o —O—(CH 2 ) p —, R 5  represents a hydrogen atom, an amino group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a C 1-6 alkylamino group, a C 1-6  alkoxycarbonylamino group, etc, or pharmaceutically acceptable salts thereof. These compounds are useful as an antiarrhythmic agent.

TECHNICAL FIELD

[0001] The present invention relates to benzopyran derivatives having aprolongation effect on the refractory period, which are used fortreatments of arrhythmia in mammals including human being.

BACKGROUND ART

[0002] As benzopyran derivatives, there have been known4-acylaminobenzopyran derivatives exemplified by Cromakalim (JapanesePatent Application Laid-Open No. Sho 58-67683). These4-acylaminobenzopyran derivatives exemplified by Cromakalim are known toopen an ATP sensitive K⁺ channel and to be effective for treatments ofhypertension and asthma, but there has not been any mention as to thetreatment of arrhythmia based on a prolongation effect on the refractoryperiod.

[0003] Now, conventional antiarrhythmic agents having a prolongationeffect on the refractory period as a main function (such as Class Idrugs of antiarrhythmic agent classification according to VaughanWilliams, or d-sotalol belonging to Class III) have highly dangerousarrhythmic inducing actions that can result in sudden death such astorsades de pointes based on extension of ventricular muscle actionpotential relating to the prolongation effect on the refractory period,which become the therapeutic problems. Thus, agents having less sideeffects are desired.

DISCLOSURE OF INVENTION

[0004] The inventors of the present invention have made an intensivesearch and study of compounds having a prolongation effect on therefractory period more selective for atrium muscle than for ventricularmuscle, and found that the compound of the formula (I) has aprolongation effect on the refractory period selective for atrium musclewithout any influence on the refractory period and action potential ofventricular muscle.

[0005] The inventors of the present invention have studied eagerlybenzopyran derivatives, and surprisingly found that the compound of theformula (I) has a strong prolongation effect on the refractory period,and that it is useful as an antiarrhythmic agent. The present inventionhas been made based on this finding.

[0006] The present invention relates to a benzopyran derivative of theformula (I)

[0007] wherein,

[0008] R¹ and R² represent each independently a hydrogen atom or aC₁₋₆alkyl group in which said alkyl group may be optionally substitutedwith a halogen atom, a hydroxyl group or a C₁₋₆alkoxy group in whichsaid alkoxy group may be optionally substituted with a fluorine atom,

[0009] R³ represents a hydroxyl group or a C₁₋₆alkylcarbonyloxy group,

[0010] R⁴ represents a hydrogen atom, or R³ and R⁴ together form a bond,

[0011] R⁶ represents a hydrogen atom,

[0012] R⁷ represents a hydrogen atom or a C₁₋₆alkyl group,

[0013] X is absent, or represents C═O or SO₂,

[0014] R⁸ represents a hydrogen atom or a C₁₋₆alkyl group in which saidalkyl group may be optionally substituted with a hydroxyl group or aC₁₋₆alkoxy group,

[0015] R⁹ represents a hydrogen atom or a nitro group,

[0016] when R⁹ represents a hydrogen atom,

[0017] Y represents a C₃₋₈alkylene group or —(CH₂)_(m)—CR¹¹R¹²(CH₂)_(n)— in which m and n represent each independently 0, 1, 2, 3 or4, and m+n is equal to or more than 2; when m represents 0, R¹¹ and R1²represent each independently a C₁₋₆alkyl group, and when m representsthose other than 0, R¹¹ and R¹² represent each independently a C₁₋₃alkylgroup or a hydroxyl group, or R¹¹ and R¹² together form a oxygen atom,

[0018] R⁵ represents a fluorine atom, a trifluoromethyl group, an aminogroup, a C₁₋₆alkylthio group, a C₁₋₆alkylamino group, adi-C₁₋₆alkylamino group, a C₁₋₆ alkylcarbonylamino group, aC₁₋₆alkylsulfonylamino group, an aminocarbonyl group, aC₁₋₆alkylaminocarbonyl group, a di-C₁₋₁₆alkylaminocarbonyl group, a C₁₋₆alkylcarbonyl group, a C₁₋₆alkoxycarbonyl group, aC₁₋₆alkoxycarbonylamino group, an aminosulfonyl group, aC₁₋₆alkylsulfonyl group, a carboxyl group or a benzoyl group in whichsaid benzoyl group may be optionally substituted with a C₁₋₆alkyl group,a C₁₋₆alkoxy group, a halogen atom, a nitro group or a cyano group, and

[0019] when R⁹ represents a nitro group,

[0020] Y represents a C4 alkylene group, —(CH₂)_(m)—CR¹¹R¹²—(CH₂)_(n)—in which m, n, R¹¹ and R¹² are same as the above or—(CH₂)_(o)—O—(CH₂)_(p)— in which o and p represent each independently 2,3 or 4,

[0021] R⁵ represents a hydrogen atom, a fluorine atom, a trifluoromethylgroup, a hydroxyl group, a formamide group, an amino group, a C₁₋₆alkoxygroup, a C₃₋₈cycloalkyl group, a C₁₋₆alkylthio group, a C₁₋₆alkylaminogroup, a di-C₁₋₆alkylamino group, a C₁₋₆alkylcarbonylamino group, aC₁₋₆alkylsulfonylamino group, an aminocarbonyl group, aC₁₋₆alkylaminocarbonyl group, a di-C₁₋₆alkylaminocarbonyl group, aC₁₋₆alkylcarbonyl group, a C₁₋₆alkoxycarbonyl group, a C₁₋₆alkoxycarbonylamino group, an aminosulfonyl group, a C₁₋₆alkylsulfonylgroup, a carboxyl group or a benzoyl group in which said benzoyl groupmay be optionally substituted with a C₁₋₆alkyl group, a C₁₋₆alkoxygroup, a halogen atom, a nitro group or a cyano group;

[0022] or a pharmaceutically acceptable salt thereof.

[0023] The compound according to the present invention has a strongprolongation effect on the refractory period and it can be used as adrug for treating arrhythmia.

[0024] Respective substituents for the compound (I) according to thepresent invention are illustrated concretely specifically as follows.

[0025] Herein, “n” means normal, “i” means iso, “s” means secondary, “t”means tertiary, “c” means cyclo, and “p” means para.

[0026] As C₁₋₃alkyl groups, there may be mentioned methyl, ethyl,n-propyl, i-propyl and c-propyl, etc.

[0027] As C₁₋₆alkyl groups, there may be mentioned methyl, ethyl,n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl,c-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl,2,2-dimethylpropyl, c-pentyl, 1-hexyl, 2-hexyl, 3-hexyl,1-methyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl,3,3-dimethyl-n-butyl and c-hexyl, etc. Preferably, there may bementioned methyl, ethyl, n-propyl, i-propyl and n-butyl.

[0028] As halogen atoms, there may be mentioned a fluorine atom, achlorine atom, a bromine atom and an iodine atom. Preferably, there maybe mentioned a fluorine atom, a chlorine atom and a bromine atom.

[0029] As C₁₋₆alkoxy groups, there may be mentioned methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy,1-pentyloxy, 2-pentyloxy, 3-pentyloxy, i-pentyloxy, neopentyloxy,2,2-dimethylpropoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy,1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy,1,2,2-trimethyl-n-propoxy and 3,3-dimethyl-n-butoxy, etc. Preferably,there may be mentioned methoxy, ethoxy, n-propoxy and i-propoxy.

[0030] As C₄₋₈alkylene groups, there may be mentioned butylene,pentylene, hexylene, heptylene and octylene, etc. Preferably, there maybe mentioned pentylene.

[0031] As C₃₋₈alkylene groups, there may be mentioned propylene inaddition to the aforementioned C₄₋₈alkylene groups. Preferably, theremay be mentioned pentylene.

[0032] As C₁₋₆alkylcarbonyloxy groups, there may be mentionedmethylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy,i-propylcarbonyloxy, n-butylcarbonyloxy, i-butylcarbonyloxy,s-butylcarbonyloxy, t-butylcarbonyloxy, 1-pentylcarbonyloxy,2-pentylcarbonyloxy, 3-pentylcarbonyloxy, i-pentylcarbonyloxy,neopentylcarbonyloxy, t-pentylcarbonyloxy, 1-hexylcarbonyloxy,2-hexylcarbonyloxy, 3-hexylcarbonyloxy, 1-methyl-n-pentylcarbonyloxy,1,1,2-trimethyl-n-propylcarbonyloxy, 1,2,2-trimethyl-n-propylcarbonyloxyand 3,3-dimethyl-n-butylcarbonyloxy, etc. Preferably, there may bementioned methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy,i-propylcarbonyloxy, n-butylcarbonyloxy and t-butylcarbonyloxy.

[0033] As C₃₋₈cycloalkyl groups, there may be mentioned c-propyl,c-butyl, c-pentyl, c-hexyl, c-heptyl and c-octyl, etc. Preferably, theremey be mentioned c-propyl, c-butyl and c-hexyl.

[0034] As C₁₋₆alkylthio groups, there may be mentioned metylthio,ethylthio, n-propylthio, i-propylthio, c-propylthio, n-butylthio,i-butylthio, s-butylthio, t-butylthio, c-butylthio, 1-pentylthio,2-pentylthio, 3-pentylthio, i-pentylthio, neopentylthio, t-pentylthio,c-pentylthio, 1-hexylthio, 2-hexylthio, 3-hexylthio, c-hexylthio,1-methyl-n-pentylthio, 1,1,2-trimethyl-n-propylthio,1,2,2-trimethyl-n-propylthio and 3,3-dimethyl-n-butylthio, etc.Preferably, there may be mentioned methylthio, ethylthio, n-propylthio,i-propylthio and n-butylthio.

[0035] As C₁₋₆alkylamino groups, there may be mentioned methylamino,ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino,i-butylamino, s-butylamino, t-butylamino, c-butylamino, 1-pentylamino,2-pentylamino, 3-pentylamino, i-pentylamino, neopentylamino,t-pentylamino, c-pentylamino, 1-hexylamino, 2-hexylamino, 3-hexylamino,c-hexylamino, 1-methyl-n-pentylamino, 1,1,2-trimethyl-n-propylamino,1,2,2-trimethyl-n-propylamino and 3,3-dimethyl-n-butylamino, etc.Preferably, there may be mentioned methylamino, ethylamino,n-propylamino, i-propylamino and n-butylamino.

[0036] As di-C₁₋₆alkylamino groups, there may be mentioneddimethylamino, diethylamino, di-n-propylamino, di-1-propylamino,di-c-propylamino, di-n-butylamino, di-1-butylamino, di-s-butylamino,di-t-butylamino, di-c-butylamino, di-1-pentylamino, di-2-pentylamino,di-3-pentylamino, di-i-pentylamino, di-neopentylamino, di-t-pentylamino,di-c-pentylamino, di-1-hexylamino, di-2-hexylamino, di-3-hexylamino,di-c-hexylamino, di-(1-methyl-n-pentyl)amino,di-(1,1,2-trimethyl-n-propyl)amino, di-(1,2,2-trimethyl-n-propyl)amino,di-(3,3-dimethyl-n-butyl)amino, methyl-(ethyl)amino,methyl(n-propyl)amino, methyl(i-propyl)amino, methyl(c-propyl)amino,methyl(n-butyl)amino, methyl(i-butyl)amino, methyl(s-butyl)amino,methyl(t-butyl)amino, methyl(c-butyl)amino, ethyl(n-propyl)amino,ethyl(i-propyl)amino, ethyl(c-propyl)amino, ethyl(n-butyl)amino,ethyl(i-butyl)amino, ethyl(s-butyl)amino, ethyl(t-butyl)amino,ethyl(c-butyl)amino, n-propyl(i-propyl)amino, n-propyl(c-propyl)amino,n-propyl(n-butyl)amino, n-propyl(i-butyl)amino, n-propyl(s-butyl)amino,n-propyl(t-butyl)amino, n-propyl(c-butyl)amino, i-propyl(c-propyl)amino,i-propyl(n-butyl)amino, i-propyl(i-butyl)amino, i-propyl(s-butyl)amino,i-propyl(t-butyl)amino, i-propyl(c-butyl)amino, c-propyl(n-butyl)amino,c-propyl(i-butyl)amino, c-propyl(s-butyl)amino, c-propyl(t-butyl)amino,c-propyl(c-butyl)amino, n-butyl(i-butyl)amino, n-butyl(s-butyl)amino,n-butyl(t-butyl)amino, n-butyl(c-butyl)amino, i-butyl(s-butyl)amino,i-butyl(t-butyl)amino, i-butyl(c-butyl)amino, s-butyl(t-butyl)amino,s-butyl(c-butyl)amino and t-butyl(c-butyl)amino, etc. Preferably, theremay be mentioned dimethylamino, diethylamino, di-n-propylamino,di-1-propylamino and di-n-butylamino.

[0037] As C₁₋₆alkylcarbonylamino groups, there may be mentionedmethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino,i-propylcarbonylamino, n-butylcarbonylamino, i-butylcarbonylamino,s-butylcarbonylamino, t-butylcarbonylamino, 1-pentylcarbonylamino,2-pentylcarbonylamino, 3-penylcarbonylamino, i-pentylcarbonylamino,neopentylcarbonylamino, t-pentylcarbonylamino, 1-hexylcarbonylamino,2-hexylcarbonylamino and 3-hexylcarbonylamino, etc. Preferably, theremay be mentioned methylcarbonylamino, ethylcarbonylamino,n-propylcarbonylamino, i-propylcarbonylamino and n-butylcarbonylamino.

[0038] As C₁₋₆alkylsulfonylamino groups, there may be mentionedmethylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,i-propyl-sulfonylamino, n-butylsulfonylamino, i-butylsulfonylamino,s-butylsulfonylamino, t-butylsulfonylamino, 1-pentylsulfonylamino,2-pentylsulfonylamino, 3-pentylsulfonylamino, i-pentylsulfonylamino,neopentylsulfonylamino, t-pentylsulfonylamino, 1-hexylsulfonylamino,2-hexylsulfonylamino and 3-hexylsulfonylamino, etc. Preferably, theremay be mentioned methylsulfonylamino, ethylsulfonylamino,n-propylsulfonylamino, i-propylsulfonylamino and n-butylsulfonylamino.

[0039] As C₁₋₆alkylaminocarbonyl groups, there may be mentionedmethylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,i-propylaminocarbonyl, n-butylaminocarbonyl, i-butylaminocarbonyl,s-butylaminocarbonyl, t-butylaminocarbonyl, 1-pentylaminocarbonyl,2-pentylaminocarbonyl, 3-pentylaminocarbonyl, i-pentylaminocarbonyl,neopentylaminocarbonyl, t-pentylaminocarbonyl, 1-hexylaminocarbonyl,2-hexylaminocarbonyl and 3-hexylaminocarbonyl, etc. Preferably, theremay be mentioned methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, i-propylaminocarbonyl and n-butylaminocarbonyl.

[0040] As di-C₁₋₆alkylaminocarbonyl groups, there may be mentioneddimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl,di-i-propylaminocarbonyl, di-c-propylaminocarbonyl,di-n-butylaminocarbonyl, di-i-butylaminocarbonyl,di-s-butylaminocarbonyl, di-t-butylaminocarbonyl,di-c-butylaminocarbonyl, di-1-pentylaminocarbonyl,di-2-pentylaminocarbonyl, di-3-pentylaminocarbonyl,di-1-pentylaminocarbonyl, di-neopentylaminocarbonyl,di-t-pentylaminocarbonyl, di-c-pentylaminocarbonyl,di-1-hexylaminocarbonyl, di-2-hexylaminocarbonyl anddi-3-hexylaminocarbonyl, etc. Preferably, there may be mentioneddimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl,di-1-propylaminocarbonyl, di-c-propylaminocarbonyl anddi-n-butylaminocarbonyl.

[0041] As C₁₋₆alkylcarbonyl groups, there may be mentionedmethylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl,n-butylcarbonyl, i-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl,1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, i-pentylcarbonyl,neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyland 3-hexylcarbonyl. Preferably, there may be mentioned methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl and n-butylcarbonyl.

[0042] As C₁₋₆alkoxycarbonyl groups, there may be mentionedmethoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl,n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl,1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl,i-pentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl,1-hexyloxycarbonyl, 2-hexyloxycarbonyl and 3-hexyloxycarbonyl, etc.Preferably, there may be mentioned methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl,i-butoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl.

[0043] As C₁₋₆alkoxycarbonylamino groups, there may be mentionedmethoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino,i-propoxycarbonylamino, n-butoxycarbonylamino, i-butoxycarbonylamino,s-butoxycarbonylamino, t-butoxycarbonylamino, 1-pentyloxycarbonylamino,2-pentyloxycarbonylamino, 3-pentyloxycarbonylamino,i-pentyloxycarbonylamino, neopentyloxycarbonylamino,t-pentyloxycarbonylamino, 1-hexyloxycarbonylamino,2-hexyloxycarbonylamino and 3-hexyloxycarbonylamino, etc. Preferably,there may be mentioned methoxycarbonylamino, ethoxycarbonylamino,n-propoxycarbonylamino, i-propoxycarbonylamino, n-butoxycarbonylamino,i-butoxycarbonylamino, s-butoxycarbonylamino and t-butoxycarbonylamino.

[0044] As C₁₋₆alkylsulfonyl groups, there may be mentionedmethanesulfonyl and ethanesulfonyl.

[0045] As preferable compounds used in the present invention, thefollowing compounds may be mentioned.

[0046] (1) The benzopyran derivative of the formula (I) orpharmaceutically acceptable salt thereof, wherein R¹ and R² represent amethyl group, R³ represents a hydroxyl group and R⁴ represents ahydrogen atom.

[0047] (2) Th e benzopyran derivative or pharmaceutically acceptablesalt thereof according to aforementioned (1), wherein X represents C═O,R⁷ represents a hydrogen atom, a nd R⁸ represents a methyl group.

[0048] (3) The benzopyran derivative or pharmaceutically acceptable saltthereof according to aforementioned (1), w herein X is absent, and R⁷and R⁸ represent a hydrogen atom.

[0049] (4) The benzopyran derivative or pharmaceutically acceptable saltthereof according to aforementioned (2), wherein R⁹ represents ahydrogen atom.

[0050] (5) The benzopyran derivative or pharmaceutically acceptable saltthereof according to aforementioned (2), wherein R⁹ represents a nitrogroup.

[0051] (6) The benzopyran derivative or pharmaceutically acceptable saltthereof according to aforementioned (3), wherein R⁹ represents ahydrogen atom.

[0052] (7) The benzopyran derivative or pharmaceutically acceptable saltthereof according to aforementioned (3), wherein R⁹ represents a nitrogroup.

[0053] Concrete examples of the compounds that can be used in thepresent invention are shown as follows, but the present invention is notlimited thereto. Herein, “Me” means a methyl group, “Et” means an ethylgroup, “Pr” means a propyl group, “Bu” means a butyl group, “Pen” meansa pentyl group, “Hex” means a hexyl group, “Ac” means an acetyl group(COCH₃), “Ph” means a phenyl group, “n” means normal, “i” means iso, “t”means tertiary, and “c” means cyclo, respectively.

R¹ R² Y R⁵ H H (CH₂)₃ NH₂ Me Me (CH₂)₅ NHMe Me Me (CH₂)₅ CO₂H Me Me(CH₂)₅ NMe₂ Me Me (CH₂)₆ COMe Me Me (CH₂)₃ CONH₂ Me Me (CH₂)₃ CO₂Et MeMe (CH₂)₄ CONHMe Me Me (CH₂)₅ NH₂ Me Me (CH₂)₆ NH₂ Me Me (CH₂)₄ COEt MeMe (CH₂)₄ CO₂Me Me Me (CH₂)₅ CO₂Me Me Me (CH₂)₄CHOH(CH₂)₂ COMe Me Me(CH₂)₄ NHMe Me Me (CH₂)₄CHMeCH₂ NH₂ Me Me (CH₂)₂CMe₂(CH₂)₂ NH₂ Me Me(CH₂)₅ CONH₂ Et Et (CH₂)₅ CONHMe Et Et (CH₂)₅ NHMe n-Pr n-Pr (CH₂)₅ NH₂i-Pr i-Pr (CH₂)₅ NH₂ n-Bu n-Bu (CH₂)₅ NH₂ i-Bu i-Bu (CH₂)₅ CONH₂ t-But-Bu (CH₂)₅ NHCOMe n-Pen n-Pen (CH₂)₅ NHCOMe n-Hex n-Hex (CH₂)₅ CONH₂CF₃ CF₃ (CH₂)₅ NH₂ CH₂OCH₃ CH₂OCH₃ (CH₂)₅ NH₂

R¹ R² R³ R⁷ X R⁸ H H OH H — H Me Me OH H — Me Me Me OH H C═O H Me Me OHH C═O Me Me Me OH H C═O Et Me Me OH H C═O n-Pr Me Me OH H C═O i-Pr Me MeOH H C═O n-Bu Me Me OH H C═O i-Bu Me Me OH H C═O t-Bu Me Me OH H C═On-Pen Me Me OH H SO₂ n-Hex Me Me OH H SO₂ Me Me Me OCOMe H SO₂ c-Pen MeMe OCOEt H C═O c-Pr Me Me OH Me — c-Bu Me Me OH Et — CH₂OCH₃ Me Me OHn-Pr — c-Hex Et Et OH i-Pr C═O Me Et Et OH n-Bu C═O Me n-Pr n-Pr OH i-BuC═O Me i-Pr i-Pr OH t-Bu C═O Me n-Bu n-Bu OH n-Pen C═O Me i-Bu i-Bu OHn-Hex C═O Me t-Bu t-Bu OH Me C═O Me n-Pen n-Pen OH H C═O Me n-Hex n-HexOH H C═O Me CF₃ CF₃ OH H C═O Me CH₂OCH₃ CH₂OCH₃ OH H C═O Me

R¹ R² Y R⁵ H H (CH₂)₃ NH₂ Me Me (CH₂)₃O(CH₂)₂ NHMe Me Me (CH₂)₃O(CH₂)₂CO₂H Me Me (CH₂)₅ NMe₂ Me Me (CH₂)₆ COMe Me Me (CH₂)₃ CONH₂ Me Me (CH₂)₃CO₂Et Me Me (CH₂)₄ CONHMe Me Me (CH₂)₅ NH₂ Me Me (CH₂)₆ NH₂ Me Me (CH₂)₄COEt Me Me (CH₂)₄ CO₂Me Me Me (CH₂)₅ CO₂Me Me Me (CH₂)₄CHOH(CH₂)₂ COMeMe Me (CH₂)₄ NHMe Me Me (CH₂)₄CHMeCH₂ NH₂ Me Me (CH₂)₂CMe₂(CH₂)₂ NH₂ MeMe (CH₂)₅ CONH₂ Et Et (CH₂)₅ CONHMe Et Et (CH₂)₅ NHMe n-Pr n-Pr (CH₂)₅NH₂ i-Pr i-Pr (CH₂)₅ NH₂ n-Bu n-Bu (CH₂)₅ NH₂ i-Bu i-Bu (CH₂)₅ CONH₂t-Bu t-Bu (CH₂)₅ NHCOMe n-Pen n-Pen (CH₂)₅ NHCOMe n-Hex n-Hex (CH₂)₅CONH₂ CF₃ CF₃ (CH₂)₅ NH₂ CH₂OCH₃ CH₂OCH₃ (CH₂)₅ NH₂

Y R⁵ (CH₂)₄ H (CH₂)₄ NH₂ (CH₂)₄ NHSO₂Me (CH₂)₄ NMe₂ (CH₂)₄ CONH₂ (CH₂)₄CO₂Et (CH₂)₄ CONMe₂ (CH₂)₄ NHCOMe (CH₂)₅ H (CH₂)₅ NHSO₂Me (CH₂)₅ NHMe(CH₂)₅ CO₂Et (CH₂)₅ c-Hex (CH₂)₅ CONHMe (CH₂)₅ CONMe₂ (CH₂)₅ NHCOMe(CH₂)₆ H (CH₂)₆ COPh (CH₂)₆ NHMe (CH₂)₆ NMe₂ (CH₂)₆ CONH₂ (CH₂)₂O(CH₂)₂H (CH₂)₃O(CH₂)₂ H (CH₂)₄O(CH₂)₂ H (CH₂)₃OCH₂ H (CH₂)₄C═OCH₂ H CHOHCH₂ HCH₂CHMeCH₂ H CH₂CMe₂CH₂ H

Y R⁵ (CH₂)₄ H (CH₂)₄ NH₂ (CH₂)₄ NHMe (CH₂)₄ NMe₂ (CH₂)₄ CONH₂ (CH₂)₄CONMe₂ (CH₂)₄ NHCOMe (CH₂)₅ SMe (CH₂)₅ NH₂ (CH₂)₅ NHMe (CH₂)₅ NMe₂(CH₂)₅ CONH₂ (CH₂)₅ CONHMe (CH₂)₅ CONMe₂ (CH₂)₅ NHCOMe (CH₂)₆ H (CH₂)₆NH₂ (CH₂)₆ NHMe (CH₂)₆ NMe₂ (CH₂)₆ CONH₂ (CH₂)₂O(CH₂)₂ H (CH₂)₃O(CH₂)₂ H(CH₂)₄O(CH₂)₂ H (CH₂)₃OCH₂ H (CH₂)₄C═OCH₂ H CHOHCH₂ H CH₂CHMeCH₂ HCH₂CMe₂CH₂ H

[0054] The compound according to the present invention has asymmetriccarbon atoms at 3-position and 4-positon, thus optical isomers thereofbased on the asymmetric carbon atoms are present, which can be used inthe application of the present invention similar to racemate. Further, acis- and trans isomer based on configuration at 3-position and4-position may be included, but the trans isomer is preferable.

[0055] Further, when the compounds can form their salts, thepharmaceutically acceptable salts thereof can be also used as activeingredients.

[0056] As pharmaceutically acceptable salts, there may be mentionedhydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates,benzoates, tartrates, phosphates, lactates, maleates, fumarates,malates, gluconates and salicylates, etc. Preferably, there may bementioned hydrochlorides, methanesulfonates and maleates.

[0057] Then, the preparation method of the compound according to thepresent invention is illustrated.

[0058] Of the compounds of the general formula (I), those wherein R⁴represents a hydrogen atom and R³ represents a hydroxyl group, which arethe compounds of formula (I-a), can be obtained by reacting a compoundof the general formula (2) with a compound (3) in an inert solvent, asshown in the following reaction scheme.

[0059] The compound of the general formula (2) can be synthesizedaccording to known methods (methods described in J. M. Evans et al., J.Med. Chem. 1984, 27, 1127; J. Med. Chem. 1986, 29, 2194; J. T. North etal., J. Org. Chem. 1995, 60, 3397; as well as Japanese PatentApplication Laid-Open No. Sho 56-57785, Japanese Patent ApplicationLaid-Open No. Sho 56-57786, Japanese Patent Application Laid-Open No.Sho 58-188880, Japanese Patent Application Laid-Open No. Hei 2-141,Japanese Patent Application Laid-Open No. Hei 10-87650 and JapanesePatent Application Laid-Open No. Hei 11-209366, etc.).

[0060] As the solvents used in the reaction of the compound of thegeneral formula (2) with the compound (3), the following may bementioned.

[0061] There may be mentioned sulfoxide type solvents exemplified bydimethylsulfoxide; amide type solvents exemplified by dimethylformamideand dimethylacetamide; ether type solvents exemplified by ethylether,dimethoxyethane and tetrahydrofuran; halogen type solvents exemplifiedby dichloromethane, chloroform and dichloroethane; nitrile type solventsexemplified by acetonitrile and propionitrile; aromatic hydrocarbon typesolvents exemplified by benzene and toluene; hydrocarbon type solventsexemplified by hexane and heptane; and ester type solvents exemplifiedby ethyl acetate. Further, the reaction can be carried out in theabsence of a solvent. Preferably, ether type solvents and nitrile typesolvents may be mentioned.

[0062] The reaction temperature is generally from −80° C. to the refluxtemperature of the reaction solvent, preferably from −10° C. to 100° C.

[0063] The molar ratio of the reaction materials is within the range of0.5-20.0, preferably 1.0-10.0, for the compound (3)/the compound (2).

[0064] An acid catalyst may be used in the reaction.

[0065] As the acid catalysts used, there may be mentioned inorganicacids exemplified by hydrochloric acid and sulfuric acid, and Lewisacids exemplified by aluminum chloride, titanium tetrachloride, borontrifluoride diethyl ether complex, perchloric acid, lithium perchlorate,lithium bromide and ytterbium trifluoromethanesulfonate, etc.Preferably, there may be mentioned lithium bromide, perchloric acid andlithium perchlorate.

[0066] Of the compounds of the general formula (I), those other than thecompounds of the formula (I-a) (the compounds wherein R³ and R⁴ togetherform a bond and the compounds wherein R⁴ represents a hydrogen atom andR³ represents a C₁₋₆ alkylcarbonyloxy group) can be prepared by themethods similar to those described in Japanese Patent ApplicationLaid-Open No. Sho 52-91866 and Japanese Patent Application Laid-Open No.Hei 10-87650, etc.

[0067] Syntheses of optically active compounds of the compounds of thegeneral formula (I) can be attained by utilizing optical resolutionmethods (Japanese Patent Application Laid-Open No. Hei 3-141286, U.S.Pat. No. 5,097,037 and European Patent No. 409,165). Further, synthesesof optically active compounds of the general formula (2) can be attainedby utilizing asymmetric synthesis methods (Japanese National PublicationNo. Hei 5-507645, Japanese Patent Application Laid-Open No. Hei5-301878, Japanese Patent Application Laid-Open No. Hei 7-285983,European Patent Application Laid-open No.535,377 and U.S. Pat. No.5,420,314).

[0068] As described above, the inventors of the present invention foundthat the compound of the formula (I) has a strong prolongation effect onthe refractory period. The prolongation effect on the refractory periodis one of the functions of antiarrhythmic action and an importantindicator that can be extrapolated to efficiency for clinicalarrhythmia. Conventional antiarrhythmic agents having a prolongationeffect on the refractory period as the main function (such as d-sotalolbelonging to Class III of the antiarrhythmic agent classificationaccording to Vaughan Williams) have highly dangerous arrhythmic inducingactions that can result in sudden death such as torsades de pointesbased on extension of ventricular muscle action potential relating tothe prolongation effect on the refractory period, which become thetherapeutic problems for arrhythmia based on atrium (such assupraventricular tachycardia, atrial flutter and atrial fibrillation).In order to solve the problems, the inventors of the present inventioncarried out searching and studying of compounds having the prolongationeffect on the refractory period more selective for atrium muscle thanfor ventricular muscle, and found that the compound of the formula (I)has the prolongation effect on the refractory period selective foratrium muscle without any influence on the refractory period and actionpotential of ventricular muscle. The difference between the findings bythe inventors of the present invention and the known techniques is toprovide the prolongation effect on the refractory period selective foratrium muscle to these compound group, which is shown by the followingfacts; there is no influence on the action potential sustaining periodof removed ventricular muscle, and there is no influence on theelectrocardiogram QT of anesthetized animal. From the above, thecompounds of the present invention have no arrhythmic inducing action inventricular muscle, thus they can provide possibilities of acontribution to more safe uses for arrhythmia based on atrium musclethan known techniques. This technique is useful for therapeutic orpreventive uses as anti-atrial fibrillation agents, anti-atrial flutteragents and anti-atrial tachycardia agents relating to paroxysmal,chronic, preoperative, intraoperative or postoperative atrialarrhythmia, prevention of proceeding to embolus based on atrialarrhythmia, prevention of proceeding to ventricular arrhythmia ortachycardia originated from atrial arrhythmia or tachycardia, andprevention of the life prognosis worsening based on the preventiveaction for atrial arrhythmia or tachycardia which can be proceeded toventricular arrhythmia or tachycardia.

[0069] The present invention provides a pharmaceutical composition orveterinary pharmaceutical composition containing a compound of thegenerally formula (I) in an effective amount for these treatments.

[0070] As administering forms of the compound according to the presentinvention, there may be mentioned parenteral administrations by means ofinjections (subcutaneous, intravenous, intramuscular and intraperitonealinjections), ointments, suppositories and aerosol, and oraladministrations by means of tablets, capsules, granules, pills, syrups,solutions, emulsions and suspensions, etc.

[0071] The aforementioned pharmaceutical or veterinary pharmaceuticalcomposition contains the compound according to the present invention inan amount of about 0.01-99.5%, preferably about 0.1-30%, of the totalcomposition weight. In addition to the compound according to the presentinvention or the composition containing the compound, otherpharmaceutically or veterinary pharmaceutically active compounds may becontained. Further, these compositions may contain the plurality ofcompounds according to the present invention.

[0072] A clinical administration amount of the compound of the presentinvention varies depending on age, weight and sensitivity of thepatient, extent of condition, etc. and an effective administrationamount is generally about 0.003-1.5 g, preferably 0.01-0.6 g, per dayfor adult. If necessary, however, the amount outside of theaforementioned range may be used.

[0073] The compound according to the present invention is formulated foradministration by conventional pharmaceutical means.

[0074] That is, tablets, capsules, granules and pills for oraladministration are prepared by using excipients such as sucrose,lactose, glucose, starch and mannitol; binders such as hydroxypropylcellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose and polyvinyl pyrrolidone; disintegrators such as starch,carboxymethyl cellulose or its calcium salt, microcrystalline celluloseand polyethylene glycol; lubricants such as talc, magnesium or calciumstearate, and silica; lubricaing agents such as sodium laurate andglycerol, etc.

[0075] Injections, solutions, emulsions, suspensions, syrups andaerosols are prepared by using solvents for the active components suchas water, ethyl alcohol, isopropyl alcohol, propylene glycol,1,3-butylene glycol and polyethylene glycol; surfactants such assorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester,polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenatedcastor oil and lecithin; suspending agents such as carboxymethyl sodiumsalt, cellulose derivatives such as methyl cellulose, tragacanth, andnatural rubbers such as gum arabic; and preserves such asp-hydroxybenzoic acid esters, benzalkonium chloride and sorbic acidsalts, etc.

[0076] For ointments that are transdermally adsorptive pharmaceutics,for example, white vaseline, liquid paraffin, higher alcohols, Macrogolointments, hydrophilic ointments and aqueous gel-type bases, etc areused.

[0077] Suppositories are prepared by using, for example, cocoa fats,polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil andPolysorbate etc.

BEST MODE FOR CARRYING OUT THE INVENTION

[0078] The present invention is illustrated in detail by the Examples asfollows, but the present invention is not limited to these Examples.

[0079] Herein, in following formulae, “Boc” means a t-butoxycarbonylgroup.

SYNTHESIS EXAMPLES Synthesis Example 1

[0080](3R*,4S*)-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-n-pentylamino-2H-1-benzopyran-3-ol

[0081] To a solution of 1.0 g (3.59 mmol) of(+)-(3R*,4R)-6-acetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran(above 99% ee) and lithium perchlorate (1.53 g, 14.36 mmol) inacetonitrile (10 mL), n-pentylamine (0.942 mL, 7.18 mmol) was added atthe room temperature and stirred at 65° C. for 3 hours. After anaddition of an aqueous saturated sodium bicarbonate solution and anextraction with ethyl acetate, it was washed with an aqueous saturatedsodium chloride solution and dried over anhydrous magnesium sulfate. Apurification by silica gel column chromatography (Hex/AcOEt=1/2) wasconducted to obtain the intended substance at 60% yield.

[0082] Yellow Amorphous Substance.

[0083]¹H-NMR (CDCl₃) δ: 0.89 (t, J=7.0 Hz, 3H), 1.22 (s, 3H), 1.30-1.36(m, 4H), 1.52 (s, 3H), 1.48-1.56 (m, 2H), 2.55-2.71 (m, 2H), 3.57 (d,J=10.1 Hz, 1H), 3.70 (d, J=10.1 Hz, 1H), 7.62 (s, 1H), 8.68 (s, 1H),10.02 (s, 1H). MS (EI) m/z; 365 [M]⁺, 308, 293 (bp).

[0084] The following compounds were obtained by the similar manner(Synthesis Examples 2-7).

Synthesis Example No. R 2

3

4

5

6

7

Synthesis Example 2

[0085] 56% yield

[0086] Yellow amorphous substance

[0087]¹H-NMR (CDCl₃) γ: 1.21 (s, 3H), 1.52 (s, 3H), 1.70 (s, 2H), 1.79(quint, J=6.1 Hz, 2H), 2.26 (s, 3H), 2.70-2.85 (m, 2H), 3.36 (s, 3H),3.54 (t, J=5.8 Hz, 2H), 3.58 (d, J=10.3 Hz, 1H), 3.71 (d, J=10.3 Hz,1H), 7.62 (s, 1H), 8.68 (s, 1H), 10.00 (s, 1H). MS (EI) m/z; 367 [M]⁺,297 (bp).

Synthesis Example 3

[0088] 23% yield.

[0089] Yellow oil substance.

[0090]¹H-NMR (CDCl₃) δ: 1.22 (s, 3H), 1.53 (s, 3H), 1.62 (s, 2H), 1.83(quint, J=6.8 Hz, 2H), 2.10 (s, 3H), 2.26 (s, 3H), 2.63 (t, J=7.0 Hz,2H), 2.68-2.86 (m, 2H), 3.60 (d, J=10.2 Hz, 1H), 3.72 (d, J=10.2 Hz,1H), 7.63 (s, 1H), 8.70 (s, 1H), 10.01 (s, 1H). MS (EI) m/z; 383 [M]⁺,220 (bp).

Synthesis Example 4

[0091] 93% yield.

[0092] Red oil substance.

[0093]¹H-NMR (CDCl₃) δ: 0.92 (t, J=7.2 Hz, 3H), 1.21 (s, 3H), 1.33-1.60(m, 4H), 1.52 (s, 3H), 2.27 (s, 3H), 2.56-2.72 (m, 2H), 3.56 (d, J=10.2Hz, 1H), 3.71 (d, J=10.2 Hz, 1H), 7.63 (s, 1H), 8.68 (s, 1H), 10.03 (s,1H).

[0094] MS (EI) m/z; 353 [M]⁺, 263, 222 (bp).

Synthesis Example 5

[0095] 96% yield.

[0096] Red amorphous substance.

[0097]¹H-NMR (CDCl₃)δ: 0.89 (s, 9H), 1.21 (s, 3H), 1.46 (t, J=8.1 Hz,2H), 1.53 (s, 3H), 2.27 (s, 3H), 2.53-2.72 (m, 2H), 3.69 (d, J=10.2 Hz,1H), 3.71 (d, J=10.2 Hz, 1H), 7.63 (s, 1H), 8.68 (s, 1H), 10.02 (s, 1H).

[0098] MS (EI) m/z; 379 [M]⁺, 260, 146 (bp).

Synthesis Example 6

[0099] 89% yield.

[0100] Yellow crystal.

[0101] m.p. 210.0-212.0° C.

[0102]¹H-NMR (CDCl₃)δ: 0.85-1.90 (m, 13H), 1.18 (s, 3H), 1.54 (s, 3H),2.25 (s, 3H), 2.76-2.85 (m, 1H), 3.08-3.18 (m, 1H), 4.05 (d, J=8.8 Hz,1H), 4.59 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 8.78 (s, 1H), 9.77 (s, 1H).MS (EI) m/z; 405 [M]⁺, 335, 292 (bp).

Synthesis Example 7

[0103] 98% yield.

[0104] Red oil substance.

[0105]¹H-NMR (CDCl₃) δ: 1.21 (s, 3H), 1.44 (s, 9H), 1.52 (s, 3H),1.52-1.61 (m, 2H), 1.63-1.74 (m, 2H), 2.27 (s, 3H), 2.58-2.71 (m, 2H),3.07-3.16 (m, 2H), 3.60 (d, J=10.1 Hz, 1H), 3.73 (d, J=10.1 Hz, 1H),7.63 (s, 1H), 8.68 (s, 1H), 10.00 (s, ₁H).

[0106] MS (EI) m/z; 466 [M]⁺, 394, 277, 70 (bp).

Synthesis Example 8

[0107]

[0108] To the compound of Synthesis Example 7 (500 mg, 1.18 mmol), ahydrogen chloride-dioxane (4 mol/L) solution (1.18 mL, 4.72 mmol) wasadded under an ice cooling, stirred for 30 minutes, then heated to roomtemperature, and stirred for another 30 minutes. An aqueous sodiumhydroxide (1 mol/L) was added thereto, an extraction was conducted withchloroform, an organic phase was washed once with an aqueous saturatedsodium chloride solution and dried over anhydrous magnesium sulfate. Asolvent was distilled off to obtain the intended substance at

[0109] 100% yield.

[0110] Yellow solid.

[0111]¹H-NMR (CDCl₃) δ: 1.19 (s, 3H), 1.50 (s, 3H), 1.55-1.67 (m, 4H),2.26 (s, 3H), 2.58-2.70 (m, 2H), 3.14 (brs, 4H), 3.64 (d, J=10.2 Hz,1H), 3.75 (d, J=10.2 Hz, 1H), 7.61 (s, 1H), 8.65 (s, 1H), 10.02 (s, 1H).

[0112] MS (EI) m/z; 394 [M]⁺, 350 (bp).

Synthesis Example 9

[0113]Trans-6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-4-n-pentylamino-2H-1-benzopyran-3-ol

[0114] To the ethanol solution (11 mL) of compound of Synthesis Example1 (550 mg, 1.51 mmol), a 35% hydrochloric acid (1.1 mL) was added atroom temperature, and refluxed for 12 hours. An aqueous saturated sodiumbicarbonate solution was added thereto, an extraction was conducted withethyl acetate, an organic phase was washed once with an aqueoussaturated sodium chloride solution and dried over anhydrous magnesiumsulfate. After distilling off the solvent, the residue was purified bysilica gel column chromatography (Hex/AcOEt=1/1) to obtain the intendedsubstance at 75% yield.

[0115] Red amorphous substance.

[0116]¹H-NMR (CDCl₃) δ: 0.91 (t, J=8.1 Hz, 3H), 1.19 (s, 3H), 1.25-1.35(m, 4H), 1.34 (s, 3H), 1.50-1.80 (m, 4H), 2.48-2.75 (m, 2H), 3.58-3.65(m, 2H), 5.70 (s, 2H), 6.81 (s, 1H), 7.59 (s, 1H).

[0117] MS (EI) m/z; 323 [M]⁺, 252 (bp).

PREPARATION EXAMPLES

[0118] Preparation Example 1

[0119] Tablet: a compound according to the invention  10 g lactose 260 gmicrocrystalline cellulose 600 g corn starch 350 g hydroxypropylcellulose 100 g CMC-Ca 150 g magnesium stearate  30 g total 1,500 g  

[0120] The aforementioned ingredients were mixed by a conventionalmethod and thereafter 10,000 sugar-coated tablets each containing 1 mgof the active ingredient per a tablet were prepared.

Preparation Example 2

[0121] Capsule: a compound according to the invention   10 g lactose  440 g microcrystalline cellulose 1,000 g magnesium stearate   50 gtotal 1,500 g

[0122] The aforementioned ingredients were mixed by a conventionalmethod and thereafter filled in gelatin capsules to prepare 10,000capsules each containing 1 mg of the active ingredient per a capsule.

Preparation Example 3

[0123] Soft capsule: a compound according to the invention   10 g PEG400   479 g saturated fatty acid triglyceride 1,500 g peppermint oil   1 g Polysorbate 80   10 g total 2,000 g

[0124] The aforementioned ingredients were mixed by a conventionalmethod and thereafter filled in No.3 soft gelatin capsules to prepare10,000 soft capsules each containing 1 mg of the active ingredient per acapsule.

Preparation Example 4

[0125] a compound according to the invention  1.0 g liquid paraffin 10.0g cetanol 20.0 g white vaseline 68.4 g ethylparaben  0.1 g 1-menthol 0.5 g total 100.0 g 

[0126] The aforementioned ingredients were mixed by a conventionalmethod to obtain 1% ointment.

Preparation Example 5

[0127] Suppository: a compound according to the invention  1 g WitepsolH15* 478 g Witepsol W35* 520 g Polysorbate 80  1 g total 1,000 g  

[0128] The aforementioned ingredients were melt-mixed by a conventionalmethod, poured into suppository containers and cooled to solidify,thereby 1,000 suppositories (1 g) each containing 1 mg of the activeingredient per a suppository were prepared.

Preparation Example 6

[0129] Injection: a compound according to the invention 1 mg distilledwater for injection 5 mL

[0130] It is used by dissolving when applied.

PHARMACOLOGICAL TEST EXAMPLE

[0131] Effects on the Effective Refractory Period

[0132] Method

[0133] Beagles were anesthetized with pentobarbital sodium and, underartificially ventilated condition, thoracotomy was conducted along themedian and the pericardium was cut open to expose the heart. ECG wasrecorded using bipolar electrodes attached to the surface of the rightatrial free wall, right atrial auricle, and right ventricular free wall.The vagal nerves were stimulated using an electric stimulation devicevia Nichrome wires inserted into the bilateral vagal nerves in the neck.The conditions for electric stimulation to the vagal nerves were setsuch that the RR intervals on ECG were prolonged by about 100 mseccompared with those before the stimulation was started.

[0134] Electric current twice as strong as the threshold was used forthe electric stimulation to the heart, and premature stimulation S2 wasapplied after giving 10 serial S1 stimulations at the basic stimulationcyclelength. To determine the effective refractory period, the S1-S2interval was reduced by 2 msec, and the effective refractory period wasdefined as the point at which responses to premature stimulation S2 werelost.

[0135] For evaluation of drug effects, the atrial and ventriculareffective refractory periods were determined before drug administration,then each compound was administrated intravenously at the dose of 0.3mg/kg, and the atrial and ventricular effective refractory periods weredetermined from 5 min after the administration.

[0136] The results were shown as prolongation time in the atrial andventricular effective refractory periods, i.e. [effective refractoryperiod after administration]−[effective refractory period beforeadministration] (msec). TABLE 1 prolongation time in effective compoundrefractory period (msec) (Synthesis Example No.) Atrium ventricle 1 40 56 23 0 9 27 3

[0137] Results

[0138] The compounds of the present invention showed an prolongationeffect on the effective refractory period selective for atrium.

EFFECTS OF THE INVENTION

[0139] Compounds according to the present invention exhibit prolongationeffect on the effective refractory period selective for atrium, thus canbe used as an anti-atrial fibrillation agents and an supraventricularantiarrhythmic agent, and are useful as pharmaceuticals. Further, sincecompounds according to the present invention have small influence onventricle, they can contribute to safe treatments of aforementionedarrhythmic conditions.

1. A benzopyran derivative of the formula (I)

wherein, R¹ and R² represent each independently a hydrogen atom or aC₁₋₆alkyl group in which said alkyl group may be optionally substitutedwith a halogen atom, a hydroxyl group or a C₁₋₆alkoxy group in whichsaid alkoxy group may be optionally substituted with a fluorine atom, R³represents a hydroxyl group or a C₁₋₆alkylcarbonyloxy group, R⁴represents a hydrogen atom, or R³ and R⁴ together form a bond, R⁶represents a hydrogen atom, R⁷ represents a hydrogen atom or a C₁₋₆alkylgroup, X is absent, or represents C═O or SO₂, R⁸ represents a hydrogenatom or a C₁₋₆alkyl group in which said alkyl group may be optionallysubstituted with a hydroxyl group or a C₁₋₆alkoxy group, R⁹ represents ahydrogen atom or a nitro group, when R⁹ represents a hydrogen atom, Yrepresents a C₃₋₈alkylene group or —(CH₂)_(m)—CR¹¹R¹²-(CH₂)_(n)— inwhich m and n represent each independently 0, 1, 2, 3 or 4, and m+n isequal to or more than 2; when m represents 0, R¹¹ and R¹² represent eachindependently a C₁₋₆alkyl group, and when m represents those other than0, R¹¹ and R¹² represent each independently a C₁₋₃alkyl group or ahydroxyl group, or R¹¹ and R¹² together form a oxygen atom, R⁵represents a fluorine atom, a trifluoromethyl group, an amino group, aC₁₋₄alkylthio group, a C₁₋₆alkylamino group, a di-C₁₋₆alkylamino group,a C₁₋₆ alkylcarbonylamino group, a C₁₋₆alkylsulfonylamino group, anaminocarbonyl group, a C₁₋₆alkylaminocarbonyl group, adi-C₁₋₆alkylaminocarbonyl group, a C₁₋₆ alkylcarbonyl group, aC₁₋₆alkoxycarbonyl group, a C₁₋₆alkoxycarbonylamino group, anaminosulfonyl group, a C₁₋₆alkylsulfonyl group, a carboxyl group or abenzoyl group in which said benzoyl group may be optionally substitutedwith a C₁₋₆alkyl group, a C₁₋₆alkoxy group, a halogen atom, a nitrogroup or a cyano group, and when R⁹ represents a nitro group, Yrepresents a C₄₋₈alkylene group, —(CH₂)_(m)—CR¹¹R¹²—(CH₂)_(n)— in whichm, n, R¹¹ and R¹² are same as the above or —(CH₂)₀—O—(CH₂)_(p)— in whicho and p represent each independently 2, 3 or 4, R⁵ represents a hydrogenatom, a fluorine atom, a trifluoromethyl group, a hydroxyl group, aformamide group, an amino group, a C₁₋₆alkoxy group, a C₃₋₈cycloalkylgroup, a C₁₋₆alkylthio group, a C₁₋₆alkylamino group, adi-C₁₋₆alkylamino group, a C₁₋₆alkylcarbonylamino group, aC₁₋₆alkylsulfonylamino group, an aminocarbonyl group, aC₁₋₆alkylaminocarbonyl group, a di-C₁₋₆alkylaminocarbonyl group, aC₁₋₆alkylcarbonyl group, a C₁₋₆alkoxycarbonyl group, a C₁₋₆alkoxycarbonylamino group, an aminosulfonyl group, a C₁₋₆alkylsulfonylgroup, a carboxyl group or a benzoyl group in which said benzoyl groupmay be optionally substituted with a C₁₋₆alkyl group, a C₁₋₁alkoxygroup, a halogen atom, a nitro group or a cyano group; or apharmaceutically acceptable salt thereof.
 2. The benzopyran derivativeor pharmaceutically acceptable salt thereof according to claim 1,wherein R¹ and R² represent a methyl group, R³ represents a hydroxylgroup and R⁴ represents a hydrogen atom.
 3. The benzopyran derivative orpharmaceutically acceptable salt thereof according to claim 2, wherein Xrepresents C═O, R⁷ represents a hydrogen atom, and R⁸ represents amethyl group.
 4. The benzopyran derivative or pharmaceuticallyacceptable salt thereof according to claim 2, wherein X is absent, andR⁷ and R⁸ represent a hydrogen atom.
 5. The benzopyran derivative orpharmaceutically acceptable salt thereof according to claim 3, whereinR⁹ represents a hydrogen atom.
 6. The benzopyran derivative orpharmaceutically acceptable salt thereof according to claim 3, whereinR⁹ represents a nitro group.
 7. The benzopyran derivative orpharmaceutically acceptable salt thereof according to claim 4, whereinR⁹ represents a hydrogen atom.
 8. The benzopyran derivative orpharmaceutically acceptable salt thereof according to claim 4, whereinR⁹ represents a nitro group.
 9. A drug characterized by comprising abenzopyran derivative or pharmaceutically acceptable salt thereofaccording to claim 1 as an active ingredient.
 10. A drug for treatingarrhythmia characterized by comprising a benzopyran derivative orpharmaceutically acceptable salt thereof according to claim 1 as anactive ingredient.